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We will now move on to the topic of drug metabolism in inflammatory disease states which,
as we will see, is applicable to a wide variety of diseases in humans.
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The symptoms of inflammation were described more than two centuries ago by Celsus,
tumor, rubor, calor and dolour,
or, swelling, redness, heat and pain.
These symptoms are the result of
a local or systemic response to infection or injury designed to
eliminate or control invading pathogens or to
allow tissue recovery and repair following injury.
But an exaggerated, inappropriate or chronic inflammatory response
can be deleterious and many human diseases have an inflammatory component.
Local inflammation is characterized by vasodilation,
neutrophil recruitment and a cascade of
pro-inflammatory cytokine and they cause node release.
The triggering events of an inflammatory response are many and varied.
But, in the case of infection usually result from the activation by microbial products of
pattern recognition receptors such as
Toll-like receptors on cells of the innate or adaptive immune systems.
Physical or thermally-derived injuries initiate inflammation by activating
mast cells in the tissues which release histamine and tumor necrosis factor alpha,
again initiating the inflammatory cascade.
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Perhaps, the first indication that inflammation could affect
drug metabolism was this publication from 1953 by Samaras and Dietz.
Analogous to the experiments we discussed earlier,
these investigators were studying the metabolism of pentobarbital in
rats by measuring the time the animals slept after a single dose of the barbiturate.
They injected the animals with trypan blue,
an activator of the immune system or saline.
They then injected pentobarbital and measured the sleeping time.
Animals treated with trypan blue slept longer than the control animals
indicating that the metabolism clearance of pentobarbital had been impaired.
Only sporadic additional contributions to
